Inhibiting discoloration of aqueous compositions containing hexamethylenetetramine 1,3-dichloropropene salts

ABSTRACT

Aqueous compositions of cis- and cis-, trans-1-(3-chloroally)3,5,7-triaza-1-azoniaadamantane chloride mixtures, which normally discolor on aging, are stabilized against discoloration by adding thereto an amine of the group of morpholine, ethylamine, Nmethylethanolamine, diethanolamine, dipropylamine, diisopropanolamine and di-sec.-butanolamine.

United States Patent 1191 Polemenakos et al.

1 Sept. 23, 1975 INHIBITING DISCOLORATION OF AQUEOUS COMPOSITIONS CONTAINING HEXAMETIIYLENETETRAMINE 1,3-DICHLOROPROPENE SALTS Inventors: Sotiros C. Polemenakos,

Framingharn; Horst G. Langer, Wayland, both of Mass.

Assignee: The Dow Chemical Company,

Midland, Mich.

Filed: Apr. 29, 1974 Appl. No.: 465,038

US. Cl. 424/249; 260/248.5; 252/401 Int. Cl. A01N 9/22; A61K 31/53; A61L 13/00 Field of Search 424/249; 260/248.5; 252/401, 405, 407

References Cited l UNITED STATES PATENTS 1/1966 Wolf et al. 260/2485 1/1968 Howard et al.. 424/177 8/1972 Liddell 21/2.7

3,758,464 9/1973 Prindle et a1. 260/2485 OTHER PUBLICATIONS Dow Chem. Co., Information booklet Dowicil 100, 1965-1968, and publication Antimicrobial Agents, section 11-4, Paint Industry, 11962-1968.

Chemical Abstracts, Vol. 74, 1971, item 31068k and Vol. 67, 1967, item 62910p.

Chemical Abstracts, Vol. 78 (1973), 1515652 and Vol. 78 (1973), 57731d.

Primary Examiner-Donald B. Moyer Attorney, Agent, or Firm-Theodore Post; C. Kenneth Bjork 2 Claims, No Drawings INHIBITING DISCOLORATION OF AQUEOUS COMPOSITIONS CONTAINING HEXAMETHYLENETETRAMINE 1,3-DICHLOROPROPENE SALTS BACKGROUND OF THE INVENTION Both cis-l-(3-chloroally)3,5,7-triaza-lazoniaadamantane chloride, commercially available as DOWICIL 200 and hereinafter referred to as Cis- Compound," and commercial cis-, transmixtures of l -(3-chloroallyl)-3,5,7triaza-1-azoniaadamantane chloride, commercially available as DOWICIL 100, containing 55% cis-isomer and 45% trans-isomer, hereinafter referred to as "Cis-,Trans-compounds," are old and successful antimicrobial agents; U.S. Pat. No. 3,228,829. They are particularly effective in aqueous dispcrsions or emulsions. Cis-Compound is used primarily in cosmetic and allied formulations. Cis-,-Trans- Compound is used in other commercial applications. Both products are prepared by reacting hexamethy lenetetramine with 1,3-dichloropropene. In making Cis-,-Trans-Compound, the hexamethylenetetramine is reacted with a commercial mixture containing cisand trans-l ,3-dichloropropene and inert material, while in the case of Cis-Compound, the cis-l ,3- dichloropropene is separated from the above mixture and reacted with hexamethylenetetramine to give Cis- Compound.

SUMMARY OF THE INVENTION Both Cis-Compound and Cis-, Trans-Compound,

when utilized in clear or light-colored formulations containing a continuous or discontinuous aqueous phase wherein the antimicrobial is present primarily in the aqueous phase, visibly yellow on aging. This is an undesirable phenomenon, especially for the cosmetic industry.

The present invention prevents such discoloration by adding to aqueous formulations containing Cis- Compound or Cis-, Trans-Compound an amine of the group, morpholine, ethylamine, N- methylethanolamine, diethanolamine, dipropylamine, diisopropanolamine or di-sec.-butanolamine. Advantageously, the range of color inhibition is between I to 5 weight parts of amine per part of Cis-Compound and vice versa. Two to one weight parts of amine per part of CisCompound and vice versa is preferred. One to one weight parts of amine to Cis-Compound are especially preferred.

While the phenomenon which gives rise to color formation in aqueous compositions containing Cis- Compound or Cis-, Trans-Compound is not completely :understood, it is believed that Cis-Compound undergoes a slow hydrolysis to yield chloroallyl alcohol which is slowly oxidized to chloroallyl aldehyde. One of -the reactions which the latter could undergo would be aldol condensation followed by dehydration to give colored species. Another reaction could be polymerization across the double bond. It is possible that both of these reactions could take place, giving a more complicated group of products. While it is not desired to be bound by these theoretical considerations, they do explain the color formation which occurs in aqueous formulations containing Cis-Compound and are consistent with observed results.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the preparation of aqueous industrial compositions such as adhesives based on starches, animal glues, natural and synthetic gums, polyvinyl acetate and natural rubber, or emulsifiable metal-cutting fluids, cellulosethickened latex paints, coatings, sizings and printing colors for pulp and paper manufacturers, or rayonspinning emulsions, finishing solutions and printing pastes used by textile producers and the like, a substantially equal weight part of one of the amines and of Cis- Compound or Cis-Trans-Compound is used in the formulation, the formulation generally containing from about 0.05 to about 0.5 weight percent of amine, and of Cisor Cis-, Trans-Compound based on total composition. Advantageously, the amine is added to the aqueous solution or formulation as soon as it is made, and, for best results, as soon as possible after the antimicrobials, Cisor Cis-, Trans-Compound, are added to a water-containing formulation. In. all other respects, the preparation of the above-mentioned compositions need not be changed. If desired, the aqueous phase maybe buffered to an appropriate pH, e.g., between 6 and 8. However, buffering is not essential to the practice of this invention.

The following additional description and examples further describe the invention and the manner and process of making and using it to enable the art-skilled to make and use the same, and set forth the best mode contemplated by the inventors of carrying out the invention.

EXAMPLE I (a) Two sets of aqueous solutions were prepared. One contained 1% Dowicil 200 and 1% of the amine to be tested. The other set contained 1% Dowicil 200 and was used as the control.

To expedite the experiment all solutions were subjected to accelerated aging at 50C. This procedure is widely practiced in the cosmetic industry with the rule of thumb being that three weeks aging at 50C. corresponds to one year's aging at room temperature.

With the three secondary alkanolamines, diethanolamine, di-sec.-butanolamine and diisopropanolamine, after 72 hours at 50C. the Dowicil 200 solutions had remained colorless, for all practical purposes, whereas the control solutions were intensely yellow. Further experiments showed that the 1% Dowicil 200 solutions turned intensely yellow overnight. The initial solutions containing the alkanolamines were kept in the 50C. oven indefinitely to be examined periodically. Their color became a faint yellow after a few months and after four and one-half months they were still faint yellow and far better than the twenty four hour old solution of Dowicil 200.

EXAMPLE 1 (b) Cis-Compound (1 percent by weight) and an amine (l percent by weight), as specified below, were dissolved in a strongly buffered system (pH 5.5, prepared by adding 50 ml. 1N NaOH to 500 ml. 1N KH PO refluxing (-C.) for 10 minutes, cooling and visually comparing the intensities of the yellow color generated. Two controls were used for comparison, one percent Cis-Compound in the buffer solution and one percent Cis-Compound in deionized H O alone (pH -6). Even under the extremely accelerated nature of these tests, (high temperature and high concentration), the solutions with diethanolamine, morpholine, N-methylethanolamine or diisopropanolamine performed much better than the control, i.e., were only slightly yellow as compared to the intense yellow color observed for the control systems. On continued heating, the diethanolamine-inhibited CisrCompound solution did become more intensely yellow, but the time required to equal the controls was 3-4 times greater. It was noted that the unbuffered control solution on repeated runs always became more intensely yellow than all the buffered solutions. A 0.1 molar buffer is more appropriate since 1 percent by weight Cis-Compound is approximately 0.04 molar and the amines were in the range of 0.01-0.04 M. As is apparent from the preceding example, buffering is not necessary to the practice of this invention.

EXAMPLE 2 TABLE 1 Continued The flasks were stirred and their contents divided into three sterile petri plates, giving a triplicate sample for each concentration.

When the agar had solidified, each plate was insulted with 0.1 ml. of a pool of two organisms, Pseudomonas aeruginosa and Klebsiella pneumoniae, the two species being present in equal concentrations and the total count being approximately 2 X 10 org/ml. After streaking, the plates were incubated for four days, then examined for growth.

The experiment was repeated. using the same stock solutions after aging them one, four and fourteen days. The procedure was the same with the exception that the concentration range was extended to include 100, 200 and 300 ppm of Cis-Compound and Cis- Compound DEA.

The results of all four experiments are summarized in the following Table 2.

Absorbance (4000A) of Aqueous Cis-Compound 1% Solutions at 54C.

Time, hours DEA Added Solution 0 3 6 12 24 48 72 96 0.00 1 0.01 0.39 0.88 1.42 1.53 0.95 0.69 0.55 0.25 11 0.00 0.22 0.51 0.79 0.89 0.66 0.50 111 0.01 0.12 0.25 0.39 0.59 0.51 0.45 0.41 1.00 IV 0.00 0.10 0.15 0.25 0.39 0.38 .2.00 I v 0.00 0.05 0.09 0.17 0.29 0.29 0.31 0.30 0.00 Vl* 0.03 0.18 0.40 0.89 1.60 2.40 2.60

'Unhuffered solution There was an inverse correlation between the amount TABLE 2 of DEA added and the maximum intensity of the yellow colon lnhiby. Concn., ppm

- Example 3 Time, each. CisCompound lnhiby. Concn.. ppm 1 days DEA Cis-Compound This example shows that the amme stabilizer does not have any substantial effect on the antimicrobial. 288 288 A 2,000 ml. portion of nutrient agar was prepared by 4 600 700 hydrating 46 ml. of dry powder and heating it with ap- 14 700 300 proximately 2,000 ml. of water until all the agar had dlssglv'edfhgmedlately afier gfi l As shown in the Table, the activity of the mixture of F 2; z zg E 2 T i g lz" 50 aged or freshly prepared Cis-Compound DEA was 5 th yer a I a l l c e as similar to that of Cis-Compound alone. With increased con ammg h ll l pg l: a I 1 z aging, the concentrations necessary for inhibition conig at lg f t e 5 verge until there is an inversion around the eighth day. agar t erma 1 Hum was redo e t e as 5 On the fourteenth day, when the last experiment was were weighed and returned to the constant temperaperformed required 800 ppm cis compound to g gfn i l ng z sd s i ggr r ngtfis gg e rfe i hibit growth when DEA was present. By this time, how- Com ound and 10 ercent DEA stock sohi tion needed ever a Substantial portion of the cis-compound had h f n P dd d reacted with the OH present to form the corresponding 8 ma 8 a k Owmg concentrations were a e to carbinolamine, as was evident from the oil that had t e Sevem formed in the 10 percent Cis-Compound X DEA stock TABLE 1 solution utilized. It appears that the hydroxyl ion concentration resulting from the presence of 10 percent Cis-Compound DEA. ppm each CisCompound. ppm DEA raised the pH high enough to cause the decomposition of Cis-Compound to the corresponding car- ;88 binoalmine. Even though the carbinolamine that was- 600 600 formed has been found to have antimicrobial activity Z 83 comparable with Cis-Compound, its low solubility in 900 900 water renders part of it useless in the agar, and explains why the activity of the Cis-Compound DEA mixture 'drops more that that of Cis-Compound alone after 8 days. This will not be a problem in cosmetic formulations where the pH is conventionally maintained near neutral, or in dilute aqueous solutions where a small fraction of the amount of DEA is conventionally added. Equal amounts by weight of morpholine, ethylamine, N-methyethanolamine, dipropylamine, diisopropanolamine, and di-sec.-butanolamine give substantially similar results when substituted for DEA.

EXAMPLE 4 20 g. Cetyl alcohol 40 g. Lanolin 120 g. Stearic acid 80 g. Glycerin 30 g. Tricthanolamine 37l0 g. Water 4000 g. Lotion Oil phase Aqueous phase Tests were run in parallel on lotions A and B, one set of samples being treated with Cis-Compound alone, and another set of samples being treated with an equal amount of a mixture of equal weight parts of Cis- Compound and DEA, in amounts from 100 to 1,000 ppm in increments of 100 ppm.

All test samples were insulted with 0.1 ml. of a pool of the following nine organisms: Bacillus cereus, Bacillus subtilis, Escherichia coli, Klebsiella pneumioniae, Pseudonomas aeruginosa PRD- l O, Pseudomonas aeruginosa, Proteus vulgaris, Salmonella cholerasius and Staphylococcus aureus. The total count of this pool was approximately org/ml. After inoculation, the samples were incubated for 24 hours at 30C., then were streaked in triplicate on sterile nutrient agar plates. These were in turn incubated for 48 hours, then examined for growth.

The results were as follows, indicating growth and indicating no growth:

The small difference in concentration of Cis- Compound necessary to kill the organisms in the two formulations is probably due to the fact that the organisms are effected slightly differently by the ingredients in the two formulations. The data show that Cis- Compound performed as an antimicrobial similarly in the individual formulations, whether DEA was present or not. This indicates that when DEA was added to a formulation to stabilize against the discoloration of Cis- Compound, it did not effect its antimicrobial activity.

EXAMPLE 5 Aqueous solutions of Cis-Compound or Cis-Trans- Compound, each solution containing from about 0.05 to about 0.5 weight percent of Cis-Compound or equivalent amount of Cis-Trans-Compound and an equal amount by weight of one of the amines morpholine, ethylamine, N-methylethanolamine, DEA, dipropylamine, diisopropanolamine or di-sec.-butanolamine is resistant to yellowing on aging to room temperature for 6 months. Continued aging at room temperature up to 2 years gives at most a slight yellow coloration, as compared with controls which exhibit strong yellow coloration after six months and intense yellow coloration at two years.

The range of color inhibiting proportions was found to be five parts to one part, by weight, of Cis- Compound to the amine and vice versa. A two to one weight ratio of Cis-Compoundl t0 amine and vice versa was preferred and a one to one weight ratio was especially preferred.

In those instances therein an aqueous formulation reacts with or vitiates the effect of one of the amines, as determined by an accelerated aging test at 50C., it is relatively simple to reformulate, substituting a functional equivalent for the material which vitiates the effect of the amines.

What is claimed is:

1. An aqueous solution consisting essentially of about 0.05 to about 0.5 weight percent, solution basis, of cisl-( 3-chloroallyl )-3,5,7-triazal -azoniaadamantane chloride and, as a color-stabilizing agent for the said chloride to prevent yellowing, a substantially equal weight of an amine of the group morpholine, ethylamine, N-methylethanolamine, diethanolamine, dipropylamine, di-isopropanolamine and di-sec.- butanolamine.

2. A method for preventing yellowing of an aqueous solution consisting essentially of about 0.05 to about 0.5 weight percent of an antimicrobial preservative, cis-1-(3chloroallyl)-3,5,7-triaza-l-azoniaadamantane chloride, by adding thereto a substantially equal weight of an amine of the group morpholine, ethylamine, N- methylethanolamine, diethanolamine, dipropylamine, diisopropanolamine and di-sec.-butanolamine. 

1. AN AQUEOUS SOLUTION CONSISTING ESSENTIALLY OF ABOUT 0.05 TO ABOUT 0.5 WEIGHT PERCENT, SOLUTION BASIS, OF CIS-1-(3CHLOROALLY)-3,5,7-TRIAZA-1-AZONIAADAMANTANE CHLORIDE AND, AS A COLOR-STABILIZING AGENT FOR THE SAID CHLORIDE TO PREVENT YELLOWING, A SUBSTANTIALLY EQUAL WEIGHT OF AN AMINE OF THE GROUP MORPHOLINE, ETHYLAMINE, N-METHYLETHANOLAMINE, DIETHANOLAMINE, DIPROPULAMINE, DI-ISOPROPANOLAMINE AND DI-SECBUTANOLAMINE.
 2. A method for preventing yellowing of an aqueous solution consisting essentially of about 0.05 to about 0.5 weight percent of an antimicrobial preservative, cis-1-(3-chloroallyl)-3,5,7-triaza-1-azoniaadamantane chloride, by adding thereto a substantially equal weight of an amine of the group morpholine, ethylamine, N-methylethanolamine, diethanolamine, dipropylamine, diisopropanolamine and di-sec.-butanolamine. 